Smallpox is a top bioterrorism concern. Smallpox is a highly lethal viral infection of humans (30% mortality), which can spread rapidly through a population. Furthermore, there is an active smallpox vaccination campaign in the USA military, and VIG (Vaccinia Immune Globulin) is used to treat rare severe side effects of vaccination. VIG can also be used to treat smallpox infections. Problems with VIG-particularly the small number of VIG doses available and their limited potency-have led to great interest in the development of a better anti-vaccinia and anti-smallpox immunotherapy. Indeed, the NIAID High Priority Biodefense Products list includes "High titer/concentrated Vaccinia Immune Globulin (VIG) or replacement product based on monoclonal antibodies (mAbs)" as the first desired biodefense product. Our project goal is to develop a highly efficacious, highly standardized mAb replacement of VIG that can be produced in large quantities and stored long term. Fully human mAbs are the best possible form of mAbs for use in humans, eliminating all xeno / rejection issues. Gemini Science, Inc. has transgenic mice possessing the human immunoglobulin loci and thereby produce fully human antibodies. We have used these mice to develop fully human anti-poxvirus monoclonal antibodies that neutralize vaccinia virus in vitro and are protective in vivo in preliminary experiments. We will now fully demonstrate efficacy of these anti-poxvirus monoclonal antibodies in vitro and in vivo, and scale up production of sufficient mAbs to complete all preclinical testing and IND filing. Licensure of a mAb VIG replacement therapeutic product should be based on a demonstration of equal or better activity ("noninferiority") of the mAbs in the same in vivo and in vitro assays used to validate VIG for licensure, and a demonstration of superiority to VIG in safety, dosing, and product manufacturing features (e.g., ability to standardize the mAb product and produce it in large quantities). Our human anti-poxvirus mAbs are likely to succeed by all of these criteria.